Benzothiazine and benzothiazepine compounds



United States Patent 3,089,872 BENZOTHIAZINE AND BENZOTHIAZEPINECOMPOUNDS John Krapcho, New Brunswick, N.J., assignor to Olin MathiesonChemical Corporation, New York, N.Y., a corporation of Virginia NoDrawing. Filed Mar. 31, 1961, Ser. No. 99,694 9 Claims. (Cl. Mil-239.3)

This invention relates to benzothiazine and benzothiazepine compounds.More particularly, this invention relates to bases having the followingformula i X G wherein R represents lower alkyl, lower alkenyl, aralkylor aralkenyl; R represents hydrogen and lower alkyl; X representshydrogen, lower alkyl, halogen, halo-lower alkyl or lower alkoxy; Arepresents lower alkylene and N=B represents a basic nitrogen radicalselected from the group consisting of amino, (lower alkyl)arnino, di-(lower alkyl)amino, (hydroxy-lower alkyl)amino, di(hydroxy-loweralkyl)amino and saturated 5 to 6 membered monocyclic heterocyclicradicals of less than twelve carbon atoms; and n represents 0 or 1, atleast one :1 representing O, and to acid addition salts of such bases.

The terms lower alkyl, lower alkoxy" and lower alkylene include bothstraight and branched chain radicals of less than 8 carbon atoms, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,amyl, methoxy, ethoxy, propoxy, isopropoxy, ethylene, propylene and thelike. The term lower alkenyl refers to straight and branched chainunsaturated hydrocarbon radicals of less than 8 carbon atoms such asallyl, butenyl, isobutenyl and the like. The aralkyl groups representedby the symbol R include monocyclic aralkyl groups such as phenyl-loweralkyl groups wherein the lower alkyl group is the same as defined above.The aralkenyl groups represented by R are monocyclic aralkenyl groupssuch as phenyl-lower alkenyl wherein the alkenyl group is the same asdefined above, eg cinnamyl. The halo-lower alkyl groups may bemonohalogenated such as chloromethyl or polyhalogenated such as trifiuoromethyl which is preferred. All four halogens are contemplated bythe symbol X. The symbols n, in representing 0 or I, will give rise to asix-membered ring when both symbols represent 0 and a seven-memberedring when one :1 represents 0 and the other n represents 1.

Saturated five to six membered monocyclic heterocyclic radicals of lessthan 12 carbon atoms are exemplified by piperidino, (loweralkyl)piperidino, di(lower alkyl)- piperidino, (lower alkoxy)piperidino,pyrollidino, (lower alkoxylpyrollidino, morpholino, (loweralkyl)morpholino, di(lower alkyl) morpholino, (lower alkoxy)morpholino,thiamorpholino, (lower alkyl)thiamorpholino, di(loweralkyl)thiamorpholino, (lower alkoxy)thiamorpholino, piperazino, (loweralkyl)piperazino, (e. g., N methylpiperazino), di(lower alkyl)piperazinoand (lower alkoxy pi perazino.

Particularly preferred compounds are those wherein X is hydrogen orchloro, R is phenyl, A is ethylene or propylene and N=B is di(loweralkyl)amino.

The bases of this invention form acid addition salts with organic andinorganic acids. Acids useful for pre- "ice paring these acid additionsalts include for example inorganic acids, such as the hydrohalic acids(erg. hydrochloric, hydrobrornic, etc.), sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as oxalic, maleic,tartaric, citric, acetic, succinic and the like.

The compounds of this invention, including the acid addition salts,affect the central nervous system and may be used as anorectics orcentral nervous system stimulants. They maybe administered orally byincorporating a therapeutic dosage of the base or pharmaceuticallyacceptable acid addition salt in conventional dosage forms such astablets, capsules, suspensions or the like.

The compounds of Formula I can be prepared by reacting a compound havingone of the following formulas CIIR CHE X N-C=O It with an alkali metalcompound such as sodamide, sodium hydride, or triphenylmethyl sodium andthe resulting sodium salt is treated with R-halogen. This introduces thegroup represented by R on the nitrogen in the ring. Formation of thealkali metal salt with an alkali metal compound. Such as thoseenumerated above and then reaction with a compound of the formulaproduces compounds of the Formula I.

These reactions are best effected at elevated temperatures, e.g. withinthe range of about 60 C. to the reflux temperature of the solvent.Non-polar solvents, such as ether, diethylene glycol, dimethyl ether andhydrocarbons such as benzene, toluene, xylene and the like arepreferably utilized as reaction media. When compounds with aseven-membered ring system are used, it is generally preferable to usemilder temperatures.

To form the acid addition salts, the free base initially formed isreacted with at least one equivalent of the appropriate acid.

The starting materials of Formulas II, III and IV may be produced,respectively, from a Z-aminothiophenol of the formula by heating with ana-halophenylacetic acid of the for- [c.g. according to Ber. 30, 2 3(1897)], or with a cinnamic acid of the formula (vm RLCGX OCH or with anu-phenylacrylic acid of the formula (VIII) ROH (e.g. according to J.Chem. Soc. 1927, p. 2738). The symbols have the same meaning definedpreviously and Hal designates a halogen, prefrerably bromine.

Starting materials include for example, 2-phenyl-2H- 1,4 benzothiazine 3(4g) one, 2 (0 chlorophenyl)- 2H-1,4 benzothiazine 3(4g) one, 2 (pchlorophenyl) 2H 1,4 benzothiazine 3(411) one, 6 trifiuoromethyl 2phenyl 2H 1,4 benzothiazin-3(4g)- one, 2,3 dihydro 2 phenyl 1,5benzothiazepin- 4(5H)-one, 2-(p-tolyl) 3 methyl 1,5 benzothiazepin- 4(5I one, 2 (o chlorophenyl) 2,3 dihydro 1,5- benzothiazepin 4(5g) one, 2(p chlorophenyl)-2,3- dihydro 1,5 benzothiazepin 4(5I )-one, 2(pmethoxyphenyl) 2,3 dihydro 1,5 .henzothiazepin- 4(5I one, 2 (pchlorophenyl) 7 trifluoromethyl- 2,3 dihydro1,5-benzothiazepin-4-(5g)-one, Z-phenyl-S- trifluoromethyl-2,3 dihydrol,5-benzothiazepin-4(5 I1)- one, 2,3-dihydro-2-methyl-3-phenyl-1,5benzothiazepin- 4(5g) one, 2,3 dihydro 3 phenyl 1,5 benzothiazepin 4(5g)one, 7 chloro 2,3 dihydro 3- phenyl 1,5 benzothiazepin 4(5I 1) one, 7trifiuoromethyl 3 (p chlorophenyl) 2,3 dihydro 1,5- benzothiazepin-4-(5Ii)-one, etc.

The following examples are illustrative of the invention. Alltemperatures are stated on the centigrade scale.

EXAMPLE 1 Z-DI'meIhyIaminoethyl-4-Methyl-2-Phenyl-2H-I,4-Benz0thi'azine-3 (4H) One (a) A suspension of 7.2 g. of sodamide in 300ml. of toluene is treated with a suspension of 42.9 g. of 2-phenyl2H-1,4-benzothiazin-3 (4 Il)-one [Ber. 30, 23 (1897)] in 600 ml.of toluene. The resulting mixture is stirred and refluxed for one hourand the pale solution is cooled to room temperature, then treated with28.4 g. of methyl iodide in 100 ml. of toluene. After stirring forthirty minutes at room temperature, the reaction mixture is maintainedat 92-105 for two hours. A heavy precipitate separates from the mixture.This is cooled and treated with 200 ml. of water. The aqueous phase isdiscarded and the organic layer is washed with 50 ml. of water, thenconcentrated under reduced pressure. When the volume of the residue isreduced to about 100 m1., a heavy precipitate separates. The mixture isdiluted with 100 ml. of hexane. After cooling, the colorless product,4-methyl-2-phenyl-2H-1,4-benzothiazin-3(4)-one, is filtered and dried;yield 37.5 g., M.P. 145450". After purification from absolute alcohol,the colorless product melts at 150-152".

(b) A suspension of 3.2 g. of sodamide in 180 ml. of diethylene-glycoldimethyl ether is treated with 19.1 g. of4-methyl-2-phenyl-2H-l,4-benzothiazin-3(4H)-one and the mixture isheated at 95-405 for one hour, then cooled to room temperature. Thismixture is treated with a toluene solution of Z-dimethylaminoethylchloride (liberated from a concentrated solution of 16.0 gm. of thehydrochloride with ammonia water and extracted with toluene, followed bya brief drying over magnesium sulfate), stirred at room temperature forfifteen minutes and heated at 105 for three hours. After standingovernight at room temperature, the solvent is removed by distillationunder reduced pressure on a ste m ball!- The residue is cooled, treatedwith ml. of water and the mixture extracted several times with ether.The ether phases are combined, dried over magnesium sulfate and thenconcentrated to give 25 g. of Z-dimethylamino ethyl 4 methyl 2 phenyl 2H1,4 benzothiazine-3(4 Ii)-one. This free base is dissolved in 100 ml. ofisopropyl alcohol and treated with a solution of 7 g. of oxalic acid in50 ml. of isopropyl alcohol. The product first separates as an oil whichchanges to a pale yellow granular solid; yield 27.3 g., M.P. 112-115".This material is dissolved in 300 ml. of butanone, filtered (a smallamount of insoluble material remains) and cooled to give the oxalatehemihydrate as a colorless solid, M.P. 112-115.

EXAMPLE 2 2-(3-Dimethylamin0propyl)-4-Methyl-2-Phenyl-2H- 1,4-Benz0thiazine-3 (4H -One By substituting 3-dimethylaminopropylchloride for 2- dimethylaminoethyl chloride in part (b) of Example 1, 2(3 dimethylaminopropyl) 4 methyl 2 phenyl-ZH-1,4-benzothiazine-3(4H)-one is obtained.

EXAMPLE 3 2-(2-Diethylaminoethyl)-4-(2-Phenetlzyl) -2-Phenyl- 2H-1,4-Benz0thiazine-3 (4H -One (a) 4 (2 phenethyl) 2 phenyl 2H 1,4benzothiazine-3-(4 Ii)-one is prepared by substituting phenethyl bromidefor the methyl iodide in the procedure of Example 1(a).

(b) 2 (2 diethylaminoethyl) 4 (2 phenethyl) 2phenyl-2H-l,4-benzothiazine-3 (4H)-one hydrochloride is prepared by thereaction of the product of part (a) above with 2-diethylaminoethylchloride according to the procedure used in Example 1.

EXAMPLE 4 2-[2-(4-M0rph0linyDEthyl] -4-Merhyl-2-Phenyl-2H- 1,4-Benzothiazine-3-( 4H )-One 2 [2 (4-morpholinyl)ethyl] 4 methyl- 2phenyl-2H-1,4-benzothiazine3 (4H)-one is obtained by substituting2-(morpholinyl)ethy1 chloride for the Z-dimethylaminoethyl chloride inthe procedure used in Example 1(b).

EXAMPLE 5 2-(2-Dimethylamin0ethyl) -2,3-Dihydro-5-Methyl-2-Phenyl-L5-Benzorhiazepin-4 (511) -One (a) A suspension of 7.8 g. ofsodamide in 500 m1. of dry toluene is stirred and treated with asuspension of 51.0 g. of 2,3 dihydro 2-phenyl-1,5-benzothiazepin-4(5H)-one (J. Chem. Soc., 1927, p. 2738), and the mixture stirred forfifteen minutes at room temperature. The resulting solution is treatedwith 28.4 g. of methyl iodide and the mixture then stirred and heated at60-65" for three hours. After cooling, the mixture is treated with 200ml. of water and the product, 2,3-dihydro-5-methyl- Z-phenyl-1,5benzothiazepine-4(5g)-one, is isolated by evaporation of the toluenesolution under reduced pressure.

(12) A solution of 26.6 g. of triphenylmethyl sodium in 2 l. of ether istreated with 26.9 g. of material from part (a), the mixture is stirredfor a period of one hour and then treated with a solution of 12 g. of2-dimethylaminoethyl chloride in 200 ml. of ether. The mixture isrefluxed for three hours, cooled and treated with 100 ml. of water. Theether phase is dried over magnesium sulfate, filtered and the solventevaporated to give 2-(2-dimethylaminoethyl) 2,3 dihydro -5 methyl 1,5benzothiazepin-4(5H)-one.

5 EXAMPLE 6 2-[2-(4-Piperidin0)Ethyl]-2,3-Dihydro-5-Methyl-2- Phenyl-I,5 -Benzthiazepin-4 -(H -One By substituting Z-piperidinoethyl chloridefor the 2-dimethylaminoethyl chloride in the procedure of Example 5( b),2 [2 (4-piperidinoethyl]-2,3-dihydro-5methyl-2-phenyl-1,S-benzothiazepin-4(5H)-oue is obtained.

EXAMPLE 7 3-( 3-D imethylaminopropyl -2,3-Dihy 'r0-2 ,5 -Dimeth- 311-3-Phenyl-] ,5 -Benz0!hiazepin-4 (5H -One (a) A mixture of 20.4 g. ofa-phenylcrotonic acid and 15.7 g. of Z-aminothiophenol is heated at160175 for 45 minutes. The mixture is cooled, dissolved in 100 ml. ofisopropyl alcohol and diluted with 100 ml. of hexane. After cooling, thesolid is filtered and the material (18 g.) crystallized from 250 ml. ofisopropyl alcohol to give 14 g. of colorless 2,3-dihydro-2-methyl-3-phenyl-l,5-benzothiazepin-4(5H)-one, M.P. 200-202. Recrystallizationfrom 150 ml. of acetonitriie gives 12.0 g. of product, M.P. 206-207.

(b) A suspension of 1.2 g. of sodamide in 100 ml. of dry toluene istreated with a suspension 8.0 g. of product from part (a) in 200 ml. ofdry toluene and the mixture stirred at 60 for one hour and then treatedwith a solution of 5.0 g. of methyl iodide in 50 m1. of toluene. Thismixture is then maintained at 95-105 for four hours, cooled and treatedwith 100 ml. of water. Evaporation of the toluene under reduced pressureyields 2,3- dihydro 2,5 dimethyl 3 phenyl 1,5 benzothiazepin-4(5g)-onewhich is further purified by crystallization.

(0) Interaction of 28.3 g. of material from part (b), 2.4 g. of sodiumhydride and 12.2 g. of 3-climethylaminopropyl chloride indiethyleneglycol dimethyl ether as in part (b) of Example 1 gives3-(3-dimethylaminopropyl)- 3 phenyl 2,3 dihydro 2,5 dimethyl 1,5benzothiazepin-4(5)-0ne hydrochloride.

EXAMPLE 8 3- [Z-(Z-Pyrrolidyl Ethyl 1 -2,3-Dihydr0-2 ,5 -Dimethyl- 3-Phenyl-I ,5 -Benz0thiazepin-4 (5 H -One By substituting2-pyrrolidylethyl chloride for the 3- dirnethylaminopropyi chloride inthe procedure of Example 7(c),3-[2-(2-pyrrolidyl)ethyl]-2,3-dihydro-2,5-dimethyl 3 phenyl1,S-benzothiazepin-4(5H)one is obtained.

EXAMPLE 9 2-DimethylaminOethyl-Z-(P-Chlorophenyl -4-Bcnzyl-6-CItIor0-2H-l,4-Benzothiazine-3 (4H)-One (a) 2-amino-4-chlorothi0phenol[Farrington et al., Australian Jour. of Chem. 8, 545 (1958)] is heatedat 170 to 180 C. with ix-bromo-(p-chlorophenyl)acetic acid (prepared byrefluxing p-chloromandelic acid with hydrogen bromide in concentratedsulfuric acid) to produce 6chloro-Z-(p-chlorophenyl)-2H1,4-benzothiazine- 3(4H)one.

(b) The above product is reacted with benzyl chloride by the procedureof Example 1(a) to obtain 4-benzyl 6 chloro 2 (p chlorophenyl) 2H 1,4benzothiazine-3(4I )-one. Reaction of the latter with2-dimethylaminoethyl chloride by the procedure of Example 1(b) produces2-dimethylaminoethyl-2-(p-chlorophenyl)-4-benzyl-chloro-2H-1,4-benzothiazine-3 (4g) -one.

EXAMPLE 10 2-(2-Diethylam ino)-2-(P-Methoxyphenyl -4-Mezhyl--TrifluoromcthyI-ZH ,4-Benz0thiazine-3 (4H-) One By following theprocedure of Example 9, but substituting2-amino-4-trifiuoromethylthiophenol and a-bromo-(p-methoxyphenyl)aceticacid for Z-amino- -chlorothiophenol and a-bromo-(p-chlorophenyl)aceticacid, re-

spectively, in part (a) and methyl iodide and Z-diethylaminoethylchloride for benzyl chloride and Z-dimethylaminoethyl chloride,respectively, in part (b), 2-(2-diethylaminoethyl) 2 (p methoxyphenyl 4methyl 6-trifiu0romethyl-2H- l ,4-benzothiazine-3 (4 I I -one isobtained.

EXAMPLE 11 2- Z-Dimethylam inoethyl) 2,3 -Dihydr0-5 -Alkyl-Z-Phenyl-8-Bronw-1 ,5-Bcnzothiazepin-4 (5 H -One By reactingZ-amino-S-bromothiophenol (Australian Jour. of Chem., supra) withcinnarnic acid according to the procedure of Example 7 and furtherfollowing that procedure substituting allyl bromide for methyl iodideand Z-dimethylaminoethyl chloride for B-dimethylaminopropyl chloride,respectively yields 2-(Z-dimethylaminoethyl)-2,3-dihydro-S-allyl-2-phenyl-8-brorno 1,5 benzothiazepin- 4(5)-one.

EXAMPLE 12 3-(3-Dimethylaminopropyl) 2,3 Dihydr0-5-Methyl-3-Phenyl-7-Trifluoromethyl 1,5 Benz0lhiazepin-4(5H)- One S X \onn').

wherein R represents a member of the group consisting of lower alkyl,lower alkenyl, phenyl-lower alkyl and phenyllower alkenyl; R representsa member of the group consisting of hydrogen and lower alkyl; Xrepresents a member of the group consisting of hydrogen, lower alkyl,halogen, mono halo lower alkyl, trifiuorornethyl, and lower alkoxy; Arepresents lower alkylene; and N B represents a basic nitrogen radicalselected from the group consisting of amino, (lower alkyl)amino,di(lower alkyl)amino, (hydroxy-lower alkyl)amino, di(hydroxy-loweralkyl)amino and saturated 5 to 6-membered monocyclic heterocyclicradicals of less than 12 carbon atoms selected from the group consistingof piperidino, (lower aIkyDpiperidino, di (lower alkyl)piperidino,(lower alkoxy)piperidino, pyrolliidino, (lower alkoxy)pyrol1idino,morpholino, (lower a1- kyl)morpholino, di(lower alkyl)morpholino, (loweralkoxy) morpholino, thiamorp holino, (lower alkyl)thiamorphoiino,di(lower alkyl)thiamorpholino, (lower alkoxy)thiamorpholino, piperazino,(lower aIkyUpiperazino, di(lower alkyllpiperazino and (loweralkoxy)piperazino, and n represents an integer from 0 to l, at least onen being 0, and pharmaceutically acceptable acid addition salts of saidbases.

2. A compound of the formula S phcnyl C lower alkyl t :0 loweralkylene-N alt lower alkyl lower alkyl 3. A compound of the formula Sphenyl o lower alkyl I 31:} lower alkylene-N N lower alkyl lower alkyl4. A compound of the formula 8 phenyl \C/ lower alkyl glower alkylene-NN- :0 lower alkyl 5. A compound of the formula S phenyl 0 I filoworalkyleno N lower alkyl F30 lower alkyl N -C=O lr w0r alkyl 6. A compoundof the formula S lower alkyl (2H phenyl lower alkyl lower alkyl 7. Acompound of the formula S lower alkyl C H phenyl l C\ lower alkyl N- :0lower alkylene-N lower alkyl lower alkyl References Cited in the file ofthis patent UNITED STATES PATENTS DeStevens May 19, 1959 Laubach Oct.11, 1960 DeStevens Dec. 6, 1960 Winthrop et a1 Oct. 31, 1961 OTHERREFERENCES Unger et al.: Chem. Berichte, volume 30, pages 2393-6 Millset al.: Jour. Chem. Soc., 1927, pages 2738-53. Noller: Textbook ofOrganic Chemistry, second edition, W. B. Saunders Company, Philadelphia,Pa, (1958) page

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF BASES OF THE FORMULA